The four dengue virus serotypes (DENV1-4) cause the most important mosquito-borne viral disease of humans, with ~400 million infections annually. The mechanisms by which the host immune response to DENV provides either protection or enhancement in a subsequent infection with a different DENV serotype are poorly understood, and this has been a major hindrance in vaccine development. The suboptimal results from the first proof-of-concept dengue vaccine efficacy trial highlight the critical need t better understand the immune response to natural DENV infections and vaccine candidates and to identify robust correlates of protection. This P01 Program applies state-of-the-art immunological methods in the context of long-term ongoing clinical and epidemiological studies of natural DENV infections in Nicaragua as well as Phase 2 and 3 vaccine trials of the Takeda tetravalent live-attenuated dengue vaccine (TV-LAV). We propose to study qualitative and quantitative features of B and T cell immune responses in humans under a coordinated P01 Program including three projects: 1) B cell and antibody responses to natural dengue virus infections; 2) B cell and antibody responses following live attenuated dengue virus vaccination; 3) T cell responses following DENV natural infections and live-attenuated dengue virus vaccination. The overall hypothesis is that DENV-nave and DENV-exposed individuals develop fundamentally different protective B and T cell responses upon exposure to a new DENV infection or live vaccine. Moreover, we posit that it is the quality as well as the quantity of neutralizing antibodies that determines protective efficacy. The P01 is highly synergistic in that samples from the same individuals and/or sample sets, as well as specific assays and methodologies, are being shared among the Projects, which are supported by an Administrative Core, Immunology Core, and Clinical & Data Management Core. The P01 also leverages a number of existing grants and contracts supporting dengue studies, vaccine trials, and epitope mapping programs. We have formed a Consortium of world-renowned investigators with extensive experience and on-going programs in dengue clinical, immunological, and virological research and vaccine development - thus ensuring a high-quality successful research program, especially since the investigators have a long history of productive collaboration (>190 joint publications). The P01 should result in: 1) Improved understanding of what constitutes protective adaptive immunity in 1 and 2 DENV infections and in nave and previously DENV-exposed recipients of a dengue TVLAV, which can inform future vaccine formulations; 2) Identification of natural and vaccine-induced B cell/antibody and CD4+/CD8+ T cell correlates of protection that can be used to assess existing and future vaccines; 3) Identification of potential therapeutic monoclonal antibodies and T cell peptide vaccines; and 4) Mapping of novel epitopes and generation of recombinant viruses that can serve as new epitope-specific diagnostic tools.